This invention relates to compounds which are novel imidazo[1,2-a]pyrazines, and to the use of such compounds as CRF receptor antagonists in the treatment of various neurological disorders.
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)xe2x80x94derived peptide secretion from the anterior pituitary gland [J. Rivier et al. , Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
It has also been postulated that CRF has a role in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)].
Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
It has been further postulated that CRF has a role in immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress.
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
The following publications each describe CRF antagonist compounds; however, none disclose the compounds provided herein: WO95/10506; WO99/51608; WO97/35539; WO99/01439; WO97/44308; WO97/35846; WO98/03510; WO99/11643; PCT/US99/18707; WO99/01454; and, WO00/01675.
This invention provides a compound of the Formula (I): 
wherein: X is CHR5, NR5, O, S, S(O)n or a single bond, wherein n is equal to 0, 1 or 2; D is aryl or heteroaryl attached through an unsaturated carbon atom and wherein said aryl or heteroaryl is optionally substituted with from 1-5 A1-A5; R1 is C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C4-12 cycloalkylalkyl, NR6R7 or xe2x80x94C(R8) (R9)xe2x80x94Oxe2x80x94R10; R2 is C1-4 alkyl or C3-8 cycloalkyl, each of which is optionally substituted with from 1-3 hydroxy, halogen or C1-4 alkoxy, or wherein when X is a bond, R2 is optionally also CN, CF3, C2F5, C1-4 alkyl or C3-8 cycloalkyl, each of which C1-4 alkyl or C3-8 cycloalkyl is optionally substituted with from 1-3 hydroxy, halogen and C1-4 alkoxy; R3 and R4 are selected independently from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-5 cycloalkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, halogen, CN, or NR6R7; R5 is H, C1-4 alkyl or C3-8 cycloalkyl; R6 and R7 are each independently H, C1-4 alkyl, C1-4 haloalkyl, C2-8 alkoxyalkyl, C3-6 cycloalkyl, C4-12 cycloalkylalk aryl, aryl(C1-4 alkyl)-, heteroaryl or heteroaryl(C1-4 alkyl)-; R8 and R9 are each independently H or C1-4 alkyl, or R8 and R9 are taken together as xe2x95x90CH2, C2-4 alkenyl, C2-4 alkynyl; and, R10 is H or C1-4 alkyl. Preferred embodiments of this invention are set forth hereinbelow.
Said compounds antagonize CRF receptors, that is, they bind to the receptors such that CRF is inhibited from binding to the antagonized receptors. The compounds of this invention are thus useful as therapeutic agents in conditions characterized by excessive CRF expression, and this invention thus provides methods of treating a subject afflicted with a disorder, e.g., an anxiety- or depression-related disorder, characterized by CRF overexpression.
This invention provides a compound of the Formula (I): 
wherein the various substituents are as described hereinbelow.
R1 is C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C4-12 cycloalkylalkyl, NR6R7 or xe2x80x94C(R8)(R9)xe2x80x94Oxe2x80x94R10. R2 is C1-4 alkyl or C3-8 cycloalkyl, each of which is optionally substituted with from 1-3 hydroxy, halogen or C1-4 alkoxy, or wherein when X is a bond, R2 is optionally also CN, CF3, C2F5, C1-4 alkyl or C3-8 cycloalkyl, each of which C1-4 alkyl or C3-8 cycloalkyl is optionally substituted with from 1-3 hydroxy, halogen and C1-4 alkoxy. R3 and R4 are each selected independently from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-5 cycloalkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, halogen, CN, or NR6R7. R5 is H, C1-4 alkyl or C3-8 cycloalkyl. R6 and R7 are each independently H, C1-4 alkyl, C1-4 haloalkyl, C2-8 alkoxyalkyl, C3-6 cycloalkyl, C4-12 cycloalkylalkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl or heteroaryl(C1-4 alkyl)-. R8 and R9 are each independently H or C1-4 alkyl, or R8 and R9 are taken together as xe2x95x90CH2, C2-4 alkenyl, C2-4 alkynyl. R10 is H or C1-4 alkyl. R11 is H, C1-4 alkyl, C3-7 cycloalkyl, C4-12 cycloalkylalkyl, phenyl or benzyl, each phenyl or benzyl optionally substituted on the aryl moiety with 1-3 groups of C1-4 alkyl, halogen, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, or dimethylamino. R12, R13 and R14 are each independently H, C1-6 alkyl, C3-10 cycloalkyl, C4-16 cycloalkylalkyl or C1-4 haloalkyl.
X is CHR5, NR5, O, S, S(O)n or a single bond, wherein n is equal to 0, 1 or 2. D is aryl or heteroaryl attached through an unsaturated carbon atom, wherein said aryl is optionally substituted at any available position with from 1-5 of, and said heteroaryl is optionally substituted with from 1-4 of, A1, A2, A3, A4 and A5. A1, A2, A3, A4 and A5 are each independently H, C1-6 alkyl, C3-6 cycloalkyl, halo, C1-4 haloalkyl, cyano, nitro, xe2x80x94OR12, SH, xe2x80x94S(O)nR13, xe2x80x94COR12, xe2x80x94CO2R12, xe2x80x94OC(O)R13, xe2x80x94NR11COR12, xe2x80x94N(COR12)2, xe2x80x94NR11CONR12R14, or wherein A1, A2, A3, A4 and A5 are each independently phenyl or phenyl substituted with from 1 to 4 of C1-3 alkyl, C13 alkoxy, halo, cyano, dimethylamino, CF3, C2F5, OCF3, SO2Me or acetyl.
xe2x80x9cArylxe2x80x9d denotes either the 6-carbon benzene ring or the condensed 6-carbon rings of other aromatic derivatives (see, e.g., Hawley""s Condensed Chemical Dictionary (13 ed.), R. J. Lewis, ed., J. Wiley and Sons, Inc., New York (1997)); aryl includes, without limitation, phenyl, napthyl, indanyl and indenyl. xe2x80x9cHeteroarylxe2x80x9d rings are aryl rings in which one or more, typically from 1-4, of the ring-member carbon atoms is replace by an atom other than a carbon atom, i.e., a heteroatom (typically O, N or S). Heteroaryl includes, without limitation: pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, indazolyl, thienyl, isoxazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzsothienyl, 2,3-dihydrobenzothienyl-S-oxide, indolinyl, benzoxazolin-2-on-yl and benzodioxolanyl. xe2x80x9cAlkylxe2x80x9d means saturated hydrocarbon chains, branched or unbranched, having the specified number of carbon atoms. xe2x80x9cAlkenylxe2x80x9d means hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds, which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d means hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds, which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. xe2x80x9cAlkoxyxe2x80x9d means an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. xe2x80x9cCycloalkylxe2x80x9d means saturated ring groups, including mono-, bi- or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo, and iodo. xe2x80x9cHaloalkylxe2x80x9d means both branched and straight-chain alkyls having the specified number of carbon atoms, substituted with 1 or more halogens. xe2x80x9cHaloalkoxyxe2x80x9d means an alkoxy group substituted by at least one halogen atom. xe2x80x9cSubstitutedxe2x80x9d means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. xe2x80x9cUnsubstitutedxe2x80x9d atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is keto, then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; by xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
Preferably, R1 is xe2x80x94C(R8)(R9)xe2x80x94Oxe2x80x94R10. More preferably, presently, R8 is H, R9 is C2H5 or C3H7 and R10 is C2H5. Preferably, R2 is unsubstituted C1-4 alkyl; more preferably, presently, R2 is C2H5. R3 and R4 are preferably each H. X is preferably a single bond.
D is preferably phenyl, more preferably a phenyl group of the formula: 
wherein each of A1, A2 and A3 is selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, halogen and C1-4 haloalkyl. Even more preferably: A1 is H, CH3 or Cl; A2 is Cl, xe2x80x94OCH3 or xe2x80x94OCHF2; and, A3 is H or CH3. Most preferably, presently, A1 is Cl and A3 is H.
Each of R1-R12, X, D and A1-A5 are any of the possible members of the groups listed hereinabove for these substituents. R2, for example, being C1-4 alkyl or C3-8 cycloalkyl is each and every one of the members of these groups, i.e., is C1, C2, C3 and C4 alkyl, as well as C3, C4, C5, C6, C7 and C8 cycloalkyl. Moreover, selection of a substituent as a specific member of one of its groups does not limit the choice of the other substituents to less than all of the available selections.
R1 is preferably xe2x80x94CR8R9R10, and each of R8, R9 and R10 is preferably H, C1, C2, C3 or C4 alkyl. Moreover, each of the substituents is any one of these five possibilities independently of the identity of the other substituents. Thus, there are at least 125 groups of preferred compounds, each of which is characterized by a different, but preferred, combination of R8, R9 and R10 in R1. These groups of compounds are listed in Tables A and B (hereinbelow).
Table A specifies the identity of the substituent xe2x80x9cR8xe2x80x9d in preferred compounds provided herein; these are listed, in the top row from left to right, as H, and then C1, C2, C3 and C4 alkyl. The identity of the substituent xe2x80x9cR9xe2x80x9d in preferred compounds is also given, along the left side, from top to bottom, as H, and then C1, C2, C3 and C4 alkyl. Thus, each cell of the table identifies a specific combination of R8 and R9 in a preferred compound. Thus, each cell of the table identifies a specific combination of R8 and R9 in a preferred compound. Each cell is itself identified by an alphanumeric combination specifying the cell""s location within the table.
Table B specifies the identity of the substituent xe2x80x9cR10xe2x80x9d in preferred compounds provided hererein; these are listed, in the top row from left to right, as H, and then C1, C2, C3 and C4 alkyl. Moreover, the R8/R9 combinations set forth in in Table 1 are listed along the left side of the table, from top to bottom, in terms of their cell number from Table A (e.g., xe2x80x9cX1xe2x80x9d refers to that set of compounds wherein R8 and R9 are each H). Each cell of Table B thus specifies a specific combination of R8, R9 and R10 (e.g., xe2x80x9cB1xe2x80x9d refers to that set of compounds wherein each of R8, R9 and R10 are H).
R2 is preferably C1, C2, C3 or C4 alkyl (each being unsubstituted). Table C hereinbelow lists the combinations of each of these with each of the R8/R9/R10 combinations from Table B:
Also as described hereinabove, D is most preferably a phenyl substituted with A1 (presently preferably H or CH3), A2 (preferably Cl, xe2x80x94OCH3 or xe2x80x94OCHF2) and A3 (H or CH3). Tables D and DD hereinbelow identify individual sets of compounds containing each of the possible specific combinations of these groupings. Table D lists combinations of A1 and A3 (e.g., cell xe2x80x9cD1xe2x80x9d represents that set of compounds wherein A1 and A3 are each H); Table DD lists combinations of A1/A3 with the various presently preferred members of A2 (e.g., cell xe2x80x9cDD1xe2x80x9d represents that set of compounds wherein A2 is Cl and the A1/A3 combination is represented by cell xe2x80x9cD1xe2x80x9d (i.e., A1 and A3 are each H)):
Furthermore, as described hereinabove, this invention provides presently preferred compounds comprising combinations of any of the preferred members of R1 and R2 (identified in Table C hereinabove with the designations xe2x80x9cC1-C500) with any of the specific A1/A2/A3 combinations listed in Table DD; these R1*R2/A1*A2*A3 combinations, and hence, individual preferred compounds are listed specifically in Table E hereinbelow. Across the top row of the table, from left to right, are listed individual sets of compounds comprising combinations of the various specific, individual A1, A2 and A3 substituents of the phenyl ring D, as identified by their corresponding cell number in Table DD. The leftmost column of the table lists individual sets of compounds comprising the various specific, individual R1 and R2 substituents, as identified by their corresponding cell number in table C. In this regard, cell number C1 (and hence, compounds in which R1 is C1 alkyl, R2 is xe2x80x94CR8R9OCR10, and R8, R9 and R10 are each H) corresponds to the individual compounds listed in Table E as E1, E501, E1001, E1501, E2001, E2501, E3001, E3501, E4001, E4501, E5001 and E5501; the other cells of Table C (C2-C500) have a similar correspondence to the individual compounds listed in Table E.
In addition to the compounds described and listed hereinabove, this invention provides their corresponding pharmaceutically acceptable salt, radiolabelled, various stereoisomeric and prodrug forms. xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d of compounds of this invention are also provided herein. The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali or organic salts of acidic residues such as carboxylic acids.
Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
Pharmaceutically acceptable salt forms of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Radiolabelled compounds, i.e. wherein one or more of the atoms described are replaced by a radioactive isotope of that atom (e.g. C replaced by 14C or by 11C, and H replaced by 3H or 18F), are also provided for herein. Such compounds have a variety of potential uses, e.g. as standards and reagents in determining the ability of a potential pharmaceutical to bind to neurotransmitter proteins, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.
Each of the stereoisomeric forms of this invention""s compounds is also provided for herein. That is, the compounds can have one or more asymmetric centers or planes, and all chiral (enantiomeric and diastereomeric) and racemic forms of the compounds are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Compounds are isolated in either the racemic form, or in the optically pure form, for example, by chiral chromatography or chemical resolution of the racemic form.
Prodrug forms of this invention""s compounds are also provided for herein. Such xe2x80x9cprodrugsxe2x80x9d are compounds comprising this invention""s compounds and moieties covalently bound to the parent compounds such that the portions of the parent compound most likely to be involved with toxicities in subjects to which the prodrugs have been administered are blocked from inducing such effects. However, the prodrugs are also cleaved in the subjects in such a way as to release the parent compound without unduly lessening its therapeutic potential. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol, and amine functional groups in the compounds of Formulae (I-III).
The compounds provided herein are, for example and without limitation, made by the synthetic routes and schemes set forth hereinbelow.
Imidazo[1,2-a]pyrazines (1) of the present invention may be prepared from intermediate compounds of Formula (2) using the procedures outlined in Scheme 1. 
Compounds of Formula (2) (where L=leaving groups such as halogen) may be treated with ammonia or aqueous ammonia in the presence or absence an inert solvent such as alkyl alcohols, at reaction temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. to give products of Formula (3) (where L is halogen). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methyl-pyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), alkyl esters (preferably EtOAc) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).
The resulting intermediates (3) may then be reacted with alpha haloketone derivatives in a solvent such as aliphatic alcohols or an inert solvent at temperatures ranging from xe2x88x9220xc2x0 C. to 150xc2x0 C. to give compounds of Formula (4). Inert solvents may include, but are not limited to, polyethers (preferably 1,2-dimethoxyethane), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene).
The compounds of Formula (4) may be coupled to an aromatic compound of Formula (5) to give a compound of Formula (6), with elimination of the leaving group (L). For compound (4), L represents a halide, psuedohalide (such as mesylate, tosylate or triflate), or thiomethyl. For compound (5), L represents groups such as lithium, bromomagnesium, chlorozinc, (dihydroxy)boron, (dialkoxy)boron, trialkylstannyl and the like. The coupling reaction may be performed in the presence of an appropriate catalyst, such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,3-bis(diphenylphosphino)propane]nickel dichloride, etc. Two particularly useful methods involve the coupling of chloroheterocycles with in-situ-prepared arylzinc reagents according to the method of Negishi et al. (J. Org. Chem. 1977, 42, 1821), and the coupling with arylboronic esters according to the method of Suzuki et al. (Chem. Letters 1989, 1405). Appropriate solvents for reactions of this type usually include tetrahydrofuran, diethyl ether, dimethoxyethane, dimethylformamide, or dimethylsulfoxide. Typical temperatures range from ambient up to the boiling point of the solvent.
The compound of Formula (6) may be converted to a compound of Formula (7) by treatment with phosphorous oxyhalide in dialkylformamide. Compounds of Formula (8) may be obtained from a compound of Formula (7) by treatment with alkyllithiums, alkylmagnesiumhalides, alkyllithiumcuprates or alkylzinc reagents in an inert solvent such as tetrahydrofuran, diakylether or aromatic hydrocarbons.
The compound of Formula (8) can be converted to a compound of invention (1) by alkylating the alcohol with alkyl halides in the presence of base in an inert solvent. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride). Inert solvents include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 100xc2x0 C.
Alternatively, imidazo[1,2-a]pyrazine (1) of the present invention may be obtained by following the steps outlined in Scheme 2. A compound of Formula (4) may be converted to a compound of Formula (9) by following similar conditions for the conversion of compounds of Formula (6) to (7) outlined in Scheme 1. A compound of Formula (10) may be obtained from compound (9) by following conditions for the conversion of Formula (7) to (8) as shown in Scheme 1. Compound (10) may be alkylated to compound (11) by similar conditions outlined for Formula (8) to (1) outlined in scheme 1. Finally a compound of Formula (11) can be converted to a compound of invention (1) using the conditions for the conversion of Formula (4) to (6). 
Alternatively, imidazo[1,2-a]pyrazines of the present invention may be obtained by following the steps outlined in Scheme 3. The compound of Formula (7) may be oxidized to a compound of Formula (12) by following well known methods outlined in literature (see: Comprehensive Organic Transformations by R. C. Larock, 1989, pp 604-614). 
The compound of Formula (12) may be subjected to Wittig or Tebbe""s reaction conditions to afford a compound of Formula (13) which may be reduced to a compound of Formula (14).
The nitrogen containing side chain analogs of imidazo[1,2-a]pyrazine derivatives can be synthesized by following procedures outlined in Scheme 4. 
The compound of the Formula (3) may be converted to a 3-aminoimidazo[1,2-a]pyrazine derivative of Formula (15) by a three component condensation reaction consisting of primary amine, aldehyde and isonitriles in the presence of an acid in an inert solvent. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid. Also acids include Lewis acids but not limited to aluminum halides, borontrifluoride etherates, LiBF4, Magnesium halides, tin halides, titanium halides, titanium alkoxides, zinc halides and scandium triflates. Inert solvents may include, but are not limited to, polyethers (preferably 1,2-dimethoxyethane), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), haloalkanes or aromatic hydrocarbons (preferably benzene or toluene). The compound of Formula (15) may be converted to the compound of Formula (17) by following similar conditions outlined in Scheme 1.
Moreover, in addition to compounds made by these routes and schemes, this invention provides pharmaceutical compositions comprising pharmaceutically acceptable carriers and therapeutically effective amounts of the compounds. xe2x80x9cPharmaceutically acceptable carriersxe2x80x9d are media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals. Such media are formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted.
Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the contents of which are incorporated herein by reference.
Compounds provided herein are antagonists of receptors for corticotropin releasing factor (xe2x80x9cCRFxe2x80x9d), a 41 amino acid peptide that is the primary physiological regulator of pro-opiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. Immunohistochemical localization of CRF has also demonstrated that CRF has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
CRF concentrations have been found to be significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals afflicted with affective disorder or depression [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. Moreover, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)].
CRF produces anxiogenic effects in animals. Moreover, interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist alpha-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)]. The contents of the above-cited documents are incorporated herein by reference.
Thus, compounds provided herein which, because of their antagonism of CRF receptors, alleviate the effects of CRF overexpression are expected to be useful in treating these and other disorders. Such treatable disorders include, for example and without limitation: affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis and hypoglycemia.
This invention thus further provides a method of treating a subject afflicted with a disorder characterized by CRF overexpression, such as those described hereinabove, which comprises administering to the subject a pharmaceutical composition provided herein. Such compositions generally comprise a therapeutically effective amount of a compound provided herein, that is, an amount effective to ameliorate, lessen or inhibit disorders characterized by CRF overexpression. Such amounts typically comprise from about 0.1 to about 1000 mg of the compound per kg of body weight of the subject to which the composition is administered. Therapeutically effective amounts can be administered according to any dosing regimen satisfactory to those of ordinary skill in the art.
Administration is, for example, by various parenteral means. Pharmaceutical compositions suitable for parenteral administration include various aqueous media such as aqueous dextrose and saline solutions; glycol solutions are also useful carriers, and preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents; also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Alternatively, compositions can be administered orally in solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, stearic acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.
This invention is described in the following examples, which those of ordinary skill in the art will readily understand are not limiting on the invention as defined in the claims which follow thereafter.